We have studied a set of 40 human lobular breast cancer for LOH at various chromosome locations, including intragenic FHIT markers at chromosome 3p14.2, and for mutations of the E-cadherin gene. A significantly lower level of LOH was detected at chromosome arms, 1p, 3p, 9p, 11q, 13q and 18q in lobular compared to ductal breast tumours. On the contrary, all lobular cases were found with LOH at chromosome 16q22.1, containing the E-cadherin locus. A significant association was detected between LOH at 3p and high S phase, LOH at 9p and low ER and PgR content, and between LOH at 17p and aneuploidy. LOH within the FHIT gene was detected in 16% of the lobular cases, which is significantly lower than detected in ductal breast cancer. A significant association was found between LOH at the FHIT gene and reduced Fhit expression detected by IHC. The expression of Fhit was reduced to a similar level in lobular and ductal breast cancer. Thus, genetic alterations within the FHIT gene leading to loss of Fhit proteins may play an important role in the carcinogenesis of a significant number of lobular breast cancers, even though the frequency of alterations is lower than in ductal breast cancer. Six novel mutations were detected within the E-cadherin gene in combination with LOH of the wild type E-cadherin locus and reduced E-cadherin expression. LOH at 13q was significantly associated with LOH at 7q, LOH at 11q and E-cadherin gene mutations. We conclude that there is a molecular difference in the pathogenesis of lobular and ductal breast cancer.